Effects of Osteoblast‐Specific Gα _S Over‐Expression on Skeletal Development Using a Transgenic Mouse Model

Gα S is a heterotrimeric G protein that transduces signals from activated G protein‐coupled receptors on the cell surface to stimulate intracellular signaling cascades. In bone, Gα S is known to play a central role in mediating numerous growth and maintenance processes including bone formation and turnover. Clinically, constitutive activity of Gα S results in fibrous dysplasia of the bone, while a 50% reduction in Gα S activity results in pseudohypoparathyroidism and Albright hereditary osteodystrophy. Our lab has previously found a 6‐fold variation in Gα S protein levels in lymphocytes from children, suggesting significant variability in cellular Gα S levels amongst individuals. To examine the effects of increased osteoblastic Gα S expression on bone in vivo , we generated a transgenic mouse model of Gα S over‐expression in osteoblasts (Gs‐Tg mice) driven by the 3.6 kb Col1A1 promoter. At both the RNA and protein levels, expression of total Gα S was significantly increased specifically in bone and teeth of Gs‐Tg mice compared to wild‐type (WT) mice. Micro‐computed tomography (micro‐CT) assessment showed increased volumetric bone mineral density in trabecular bone of 9‐week old Gs‐Tg mice accompanied by increased trabecular number and bone volume. Moreover, increased cortical bone volume was observed in Gs‐Tg mice despite reduced size and increased porosity. These properties contributed to drastically increased brittleness of Gs‐Tg cortical bone displayed through mechanical testing. Static histomorphometry of long bones showed Gs‐Tg mice had increased growth plate heights and disorganization of growth plate chondrocytes. In concordance, dynamic histomorphometry of trabecular bone revealed disorganized and diffuse calcein green labelling. Follow‐up analyses revealed that the skeletal phenotype of Gs‐Tg mice was not resolved after skeletal maturity at 26‐weeks of age, with pronounced progression particularly in trabecular bone. Further accrual of trabecular bone occurred in Gs‐Tg mice, whereas a loss of bone was observed in WT mice. In Gs‐Tg long bones, an expansion of the trabecular bone into the growth plate was seen histologically accompanied by a complete disruption and loss of growth plates. In addition, bone formation was persistently disorganized and diffuse at this age. The cortical bone of 26‐week WT and Gs‐Tg mice was similar in size, however the increased porosity persisted in Gs‐Tg mice. Mechanical testing showed that cortical bone was much weaker in Gs‐Tg mice compared to WT. In summary, our findings suggest that high osteoblastic Gα S expression results in aberrant skeletal development in which bone production is favoured at the cost of bone quality. Support or Funding Information This project is funded by Canadian Institutes of Health Research (CIHR). Graduate support to LZ, CC, and AD was provided from the Department of Pharmacology and Toxicology at the University of Toronto. LZ and AD were also supported by Ontario Graduate Scholarships, as well as scholarships from the Bone and Mineral Group at the University of Toronto.

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